AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition of chromosomal instability that is clinically characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy. Mutations in the NBS1 gene located in band 8q21 are responsible for NBS. NBS is identified as entries 251260 in and 602667 in Online Mendelian Inheritance in Man.

In 1981, Weemaes et al¹ first delineated the syndrome in 2 siblings with microcephaly, short stature, skin pigmentation abnormalities, mental retardation, immunologic defects, and a high prevalence of chromosome 7 and/or chromosome 14 rearrangements in cultured lymphocytes.

In 1985, Seemanova et al² described a group of patients with an apparently new genetic disorder characterized by microcephaly with normal intelligence, cellular and humoral immune defects, and a striking predisposition to lymphoreticular malignancies. These cases were subsequently studied and found to fit into the category of NBS.

Further investigations revealed that in vitro cells derived from patients with NBS display characteristic abnormalities similar to those observed in ataxia-telangiectasia (A-T), including spontaneous chromosomal instability, sensitivity to ionizing radiation (IR), and radioresistant DNA synthesis (RDS). However, aside from immune deficiency and a predisposition for malignancies (particularly those of lymphoid origin), the clinical manifestations are distinct. Consequently, NBS has long been considered a variant of A-T.

In 1998, on the basis of cellular phenotypes and the results of somatic cell complementation studies suggesting genetic heterogeneity, Jaspers et al proposed the term A-T variants for diseases in this group of patients. The 2 distinct groups were designated as A-T variant 1 (V1) for NBS and A-T variant 2 (V2) for Berlin breakage syndrome.

Linkage studies allowed the exclusion of the gene responsible for NBS from the A-T locus on band 11q23 and from the translocation breakpoints in a Polish patient. When 2 independent groups of researchers finally mapped the gene to band 8q21 and isolated it in 1998, mutations in the single NBS1 gene were found to account for both A-T complementation groups V1 and V2.

Pathophysiology

NBS is caused by mutations in the NBS1 gene located at 8q21. The NBS1 gene product, nibrin, has been found to interact with at least 2 other proteins, hMre11 and Rad50. Nibrin plays a key role in regulating the activity of the N/M/R protein complex, which is involved in end-processing of both physiological and mutagenic DNA double-strand breaks (DSBs). DNA DSBs occur as intermediates in physiological events, such as V(D)J recombination during early B- and T-cell development and immunoglobulin class switch in mature B cells, but most frequently are generated by mutagenic agents such as IR and radiomimetic chemicals. DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally can lead to cancer. Nibrin has been shown to play a crucial role in immunoglobulin class switch recombination and maintenance of the integrity of chromosomal stability.

Because these key regulatory processes are defective in the cells of patients with NBS, chromosomal aberrations accumulate and immunodeficiency and gonadal failure occur. However, expression study of the murine NBS1 gene during mouse development provides evidence that apart from sites of physiologic DSBs in the testis, thymus, and spleen, NBS1 expression is also evident in several tissues and organs in which rejoining of DSBs is not known to occur. Specific molecular pathogenesis and gene function during organ development await further elucidation.

Mutant murine models of NBS have recently been derived. A null mutation affecting both alleles of the homologous gene, Nbn, is embryonically lethal for knockout mice. It has also been demonstrated that the expression of a truncated protein in humans is sufficient for survival.

Of particular significance was the discovery of the functional link between a network of genes that play important roles in repairing DNA damage, regulating cellular proliferation and apoptosis, and maintaining telomeric function. Defects in this network, including defects in the genes encoding ATM, NBS1, BRCA1, FANCD2, BLM, TP53, CDS1/CHK2, and others, can cause cancer.

Not all patients with the NBS-like phenotype and radiation sensitivity have a defect in the NBS1 gene. Some of these were found to have mutations in the gene encoding DNA ligase IV (LIG4). However, many have still-unknown defects.

Frequency

United States

More than 40 NBS patients have been diagnosed and molecularly confirmed within North America.

International

The total number of patients identified worldwide is systematically increasing, probably because physicians are becoming more aware of the disorder. The largest groups of patients as of April 2005 were diagnosed in Poland (97), the Czech Republic and Slovakia (37), Germany (21), and Ukraine (14). NBS has also been reported in Italy, France, Great Britain, The Netherlands, Spain, Bosnia, Croatia, Yugoslavia, Turkey, Russia, Morocco, Argentina, Chile, and New Zealand.

The total number of patients diagnosed with NBS (including those in North America) is estimated to be 200. They seem to be overwhelmingly of Slavic origin and carry a major founder mutation, 657del5, in the NBS1 gene (>90%).

The relative frequency of the 657del5 mutation in the Czech Republic, Poland, and Ukraine was studied, and it was found to be unexpectedly high in these 3 Slavic populations (a mean estimated prevalence of 1 case per 177 newborns).

Mortality/Morbidity

Malignancy is the most common cause of death in patients with NBS. The death of approximately a third of the patients has been confirmed. No more than 10 died from infections that led to fatal respiratory failure and 2 died from renal insufficiency due to amyloidosis. Two others died because of bone marrow aplasia (aplastic anemia), which is rather characteristic of another chromosomal instability syndrome, FA. All of the remaining patients died from malignancy.

Race

NBS seems to occur worldwide, with an increased prevalence among persons of Eastern European and Central European descent, particularly Czech and Polish people (founder effect).

Sex

No sex predilection is recognized for NBS.

Age

• Microcephaly, the most striking symptom of the disease, is usually present at birth or develops soon thereafter.
• Craniofacial characteristics become more obvious as patients age.
• Growth is delayed from the very earliest stages of life, in comparison with age- and sex-matched controls, but improvement of the growth rate is usually observed after age 2 years.
• Longitudinal studies of Polish patients indicate a decline in intellectual function with age. Most children tested during infancy and their preschool years have IQ scores indicative of normal or borderline intelligence. A shift toward a lower level of intellectual function is observed during their school-age years. This shift becomes more evident in patients older than 14 years; at this age, all tested patients had mild or moderate mental retardation.
• Progression of humoral immunodeficiency with time is observed in some children.
• Most malignancies develop before patients are aged 20 years (mean age, 9 y). The youngest patient recorded to have had acute lymphoblastic leukemia was a 1-year-old girl. Cancer appears prior to the diagnosis of NBS in approximately 20-30% of patients.
• Skin pigmentation abnormalities in the form of café au lait spots and/or vitiligo are present in more than half of NBS patients. Progressive vitiligo has been observed in 3 teenage patients of Polish descent.
• Gray hair, which reflects progeric changes, usually appears by adolescence or early adulthood.
• The longest known survival is 53 years, in an Italian woman, and 33 and 31 years in 2 men, Polish and Dutch, respectively (the latter both died from malignancy.)

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The patient history may reveal clues to the diagnosis, such as the following:
• • Course of pregnancy and delivery: Most children with NBS are born at term, in vertical presentation.
  • Early somatic development: Birth weight, length, and head circumference are usually significantly lower in comparison with sex-matched controls; a slow growth rate and poor weight gain is observed in infancy and early childhood.
  • Psychomotor development: Usually, no gross delay of milestones is observed during the first year of life; toddlers and preschool children are frequently hyperactive; speech delay is common.
  • Mild complications after vaccinations (ie, against polio or measles) or in the course of childhood infectious diseases (eg, varicella) are reported in some patients.
  • Recurring infections: These are mainly of the respiratory tract, urinary tract, and gastrointestinal system, and they become a problem in approximately two thirds of patients.
• The following information from the family history is also particularly important:
• • Occurrence of microcephaly or hydrocephaly in patient's siblings
  • Death of patient's siblings due to malignancy or severe infection
  • Malignancies among other family members

Physical

The main clinical manifestations of NBS include progressive microcephaly with characteristic facies, growth retardation, and impaired sexual maturation in females; recurrent infections due to a combined immune deficiency; and a strongly increased risk of developing cancer, in particular leukemia and lymphoma. Other frequently observed manifestations include skin pigmentation defects (café au lait and/or vitiligo spots) and minor limb abnormalities.

• Microcephaly
• • Microcephaly (ie, head circumference below the third percentile) is the most striking and consistent symptom of NBS. In the great majority of children, it is observed at birth; in individuals who were born with a head circumference within the reference range, progressive and severe microcephaly develops during the first months of life. However, despite severe and progressive microcephaly, neuromotor development is not disturbed; epileptic seizures are not characteristic of the disease.
  • Among the 58 patients of Polish descent whom Chrzanowska observed, the deficiency of occipitofrontal circumference ranged from -4.4 to -9 standard deviation, but the proportions among the diminished head measurements (length and breadth) were retained.
• Craniofacial characteristics
• • A sloping forehead and receding mandible, a prominent midface with a relatively long nose, upward slanting of the palpebral fissures (in most), and relatively large and dysplastic ears (in some) characterize the facial appearance in NBS, which is similar among all patients.
  • The craniofacial characteristics of NBS become more obvious with patient age, probably because of progressive microcephaly.
• Growth retardation
• • Children with NBS, in spite of being born at term, are characterized by a significantly lower birth weight and head circumference in comparison with sex-matched controls, as well as lower birth length and chest circumference.
  • The range of birth weight of Polish neonates was 1900-3600 g for females and 2170-3950 g for males.
  • After approximately a 2-year period of distinct postnatal growth retardation, a slight improvement in the growth rate (including those of body height and weight but not head circumference) is usually observed.
  • Most patients' growth is around the third percentile for height and weight; in some teenage patients, growth is between the 10th and 25th percentiles for height and weight. Young adult individuals with NBS can reach a height of approximately 165 cm (ie, approximately 50th percentile for females and less than third percentile for males; Polish data).
• Sexual maturation
• • Results of long-term follow-up in a large group of Polish patients drew attention to the poor development of secondary sex characteristics (ie, lack of development of genital organs and breasts, primary amenorrhea) in female patients with NBS who reached pubertal age.
  • Endocrinologic evaluation indicates ovarian failure (see Lab Studies).
  • Affected female patients fail to reach sexual maturity because of hypergonadotropic hypogonadism.
• Immune deficiency and recurring infections
• • Because of defective humoral and cellular immunity, NBS patients are prone to developing infections. A considerable variability in immune deficiency is observed among different patients.
  • The most common infections are respiratory tract infections (pneumonia, bronchitis) and sinusitis.
  • Recurrent bronchopneumonia may result in bronchiectasis.
  • Urinary and/or gastrointestinal tract infections and otitis media are also relatively common.
  • Opportunistic infections are rare, as they are in patients with A-T.
• Malignancies
• • Malignancy is the most common cause of death in patients with NBS.
  • The prevalence of lymphoid malignancies in individuals with NBS is unprecedentedly high compared with healthy individuals and persons with other cancer-predisposing diseases such as A-T, Bloom syndrome, and FA. To date, 40-50% of NBS patients have developed a malignancy by age 20 years, of which 85-90% are leukemias or lymphomas. The most common of these are non-Hodgkin lymphomas (the B-cell type predominates over the T-cell type), lymphoblastic leukemia (acute lymphoblastic leukemia, with both precursor B cells and T cells), and Hodgkin disease. Two cases of acute myeloblastic leukemia and a single case of T-cell prolymphocytic leukemia were also noted.
  • Among solid tumors, 2 were observed relatively frequently: medulloblastoma in 4 patients and rhabdomyosarcoma of the perianal region in 3 others. The latter, rhabdomyosarcoma arising perianally, is extremely uncommon in children; therefore, taking into account the number of NBS patients with this type of cancer, a strong association with NBS is suggested.
  • Other malignancies were present in single patients only. These included papillary thyroid carcinoma, gonadoblastoma, glioma, meningioma, neuroblastoma, and Ewing sarcoma.
• Cutaneous manifestations and hair characteristics
• • Skin pigmentation abnormalities include café au lait spots (usually 2-5 spots, irregular in shape) and/or depigmented spots, which are present in approximately half the patients.
  • In 3 Polish patients, vitiligo was observed by the time they became adolescents, with progression as they aged.
  • Less frequently, sun sensitivity of the eyelids is observed, and, occasionally, cutaneous telangiectasia (particularly on the back) is seen.
  • Multiple pigmented nevi and cavernous or flat hemangiomas can also occur.
  • One case of childhood sarcoidosis with cutaneous and ocular manifestations was observed.
  • Usually, the hair is thin in infants and toddlers, but later, improvement is observed. Early graying of hair may be observed by adolescence.
• Other developmental anomalies
• • CNS malformations are observed relatively frequently and may be more common than expected. Small frontal lobes and narrow frontal horns of the lateral ventricles were documented in all patients who underwent cranial MRI. Small brain size may be associated with other CNS developmental abnormalities, including partial agenesis of the corpus callosum, hydrocephaly, arachnoid cysts, and neuronal migration disorder (in the form of schizencephaly or pachygyria).
  • Minor skeletal anomalies, such as clinodactyly of the fifth fingers and/or partial syndactyly of the second and third toes, are encountered in approximately half the patients. Hip dysplasia, preaxial polydactyly, and sacral agenesis are less common.
  • Urogenital defects noted in several patients with NBS have included kidney pathology (eg, agenesis or hypoplasia, ectopic single kidney or dystopic kidneys), hydronephrosis, hypospadias, and cryptorchidisms.
  • Among other abnormalities, tracheal hypoplasia, cleft lip and/or palate, choanal atresia, anal atresia/stenosis, and cardiovascular defects (patent ductus arteriosus, ventricular septal defect) are reported. Polysplenia, a peculiarity with no clinical significance, is relatively frequently detected by ultrasonography.

Causes

NBS is a disease with an autosomal recessive pattern of inheritance.

• Consanguineous matings have been reported.
• The gene responsible for NBS, designated NBS1, is located on band 8q21.
• The entire gene consists of 16 exons and spans a DNA region of more than 50 kilobases.
• All disease-causing mutations identified to date have been found within exons 6-10 in the NBS1 gene and resulted in the production of a truncated protein.
• More than 90% of all patients tested are homozygous for the common mutation of Slavic origin, a 5 base-pair deletion (657del5) in exon 6 of the NBS1 gene.
• The remaining patients tested to date are either heterozygous for 657del5 and a second unique mutation (compound heterozygosity) or homozygous for a unique mutation. Ten unique mutations have been detected in various ethnic groups; see the Table in Lab Studies.
• The recent finding of the homozygous mutation 1089C>A in Pakistani NBS patients, initially diagnosed as having FA, has drawn attention to the clinical (microcephaly and congenital anomalies) and biological (increased sensitivity to both DNA cross-linking agents and IR) overlap of these 2 diseases.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Primary microcephaly
Fanconi anemia
Ligase IV (LIG4) syndrome
Seckel syndrome
Dubowitz syndrome
A-T–like disease
Congenital cytomegalovirus infection

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Basis for diagnosis
   
  • The diagnosis is based on the characteristic phenotype and laboratory results.
  • Laboratory studies helpful in diagnosing NBS include cytogenetic analysis, an evaluation of humoral and cellular immunity, and radiation-sensitivity testing.
  • Molecular genetic analysis enables definite confirmation.
• Cytogenetic analysis
   
  • Cytogenetic analysis allows detection of chromosomal instability, which is a characteristic feature of the disease, although the poor response of T lymphocytes to mitogens can often make diagnosis difficult.
  • In general, the constitutional karyotypes of patients with NBS are normal (46,XX or 46,XY). However, in a high proportion of phytohemagglutinin-stimulated lymphocytes (10-60%), spontaneous structural chromosomal rearrangements are observed (QFQ or GTG banding), as well as other aberrations such as chromatid and/or chromosome breaks and acentric fragments (after Giemsa-staining).
  • Most of these rearrangements specifically involve chromosomes 7 and 14, with breakpoints at bands 7p13, 7q35, 14q11, and 14q32, which are identical to those found in persons with A-T.
  • Immunoglobulin chain and T-cell receptor genes are located at these sites. The most frequently and constantly detected aberration is inv(7)(p13q35), followed by translocations 7/14, 7/7, and 14/14.
• Immunologic testing
   
  • Diagnostic evaluation of the immunological profile is required at the time of diagnosis. Afterwards, the evolution of humoral (every 6 mo) and cellular immunity (once a year) needs to be systematically monitored (until immunoglobulin administration or immunomodulating therapy is started).
  • Evaluation of humoral immunity should include measurements of serum immunoglobulin levels (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M) and IgG subclass levels. The most frequently observed defects are the combined deficit of IgG and IgA, followed by an isolated IgG deficiency. The most characteristic feature of humoral disturbances is a deficiency in one or more IgG subclasses, even with total IgG levels in the reference range; selective deficiency of IgG4 and IgG2 are the most common.
  • Evaluation of cell-mediated immunity should include measurements of T-cell lymphocyte subpopulations (CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD8⁺; CD4/CD45RA⁺, CD4/CD45RO⁺), B cells (CD19⁺), and natural killer cells (CD16⁺, CD56⁺) and an assessment of the proliferative response to mitogens or antigens (phytohemagglutinin, anti-CD3). T-cell immunity is impaired in most patients with NBS. The most commonly reported defects are mild-to-moderate lymphopenia, expressed as a low percentage of CD3⁺ T cells, a low proportion of CD4⁺ (helper) T cells, and a decreased CD4⁺/CD8⁺ ratio. A deficiency of CD4/CD45RA⁺ (naive) cells and an excess of CD4/CD45RO⁺ (memory) cells has been observed, and a high number of natural killer cells has been noted in a proportion of patients.
• Alpha-fetoprotein determination: Serum alpha-fetoprotein levels are within the reference range in patients with NBS, in contrast to elevated concentrations in approximately 90% of patients with A-T.
• IR and RDS sensitivity analysis
   
  
  • IR induces a variety of DNA lesions, including single-strand breaks and DSBs.
  • Some laboratories use the increased sensitivity of different types of cells (eg, lymphoblastoid cell lines [LCLs], cultured skin fibroblasts) to IR or to the radiomimetic agent bleomycin to confirm the diagnosis of NBS.
  • The increased frequency of induced chromosomal breakage in lymphocytes and fibroblasts clearly differentiates NBS cells from healthy cells. In a colony survival assay, NBS cells are 3-5 times more radiosensitive than control cells.
  • Examination of DNA replication in irradiated NBS cells, as well as cells in A-T and A-T–like disorder, reveals the phenomenon of RDS, which reflects a defect in control of the S-phase progression until the repair of DNA damage is complete.
• Immunoblotting assay: Western blotting allows demonstration of the presence or absence of the p95/nibrin protein in LCLs.
• Molecular genetic analysis
  
  
  • The cloning of the NBS1 gene, which was accomplished in 1998, provides the basis for both postnatal and prenatal diagnosis by means of mutation analysis.
  • The demonstration of disease-causing mutations in both alleles of the NBS1 gene is required for definitive confirmation of NBS.
  • In more than 90% of patients tested so far, the common 657del5 mutation is homozygous. The remaining patients have a heterozygous 657del5 deletion and a second unique mutation or a homozygous unique mutation.
  • Testing for the 657del5 mutation is available on a clinical basis (and is always performed first); tests for other mutations are used in research studies.
  • In the United States, approximately 70% of individuals tested to date are homozygous for the common allele 657del5, a further 15% are heterozygous for 657del5 and a second unique mutation, and the remaining 15% are homozygous for a unique mutation. See GeneReviews, Nijmegen Breakage Syndrome.
  • If further testing is requested, an LCL is established and the nuclear lysate is analyzed by means of Western blot for nibrin and by colony survival assay for radiosensitivity. If nibrin is absent or truncated and the cells are sensitive to IR, DNA is analyzed by direct sequencing for NBS1 mutations.
  NBS1 Gene Pathogenic Molecular Variants

  Mutation	Exon	Mutation Type	Change in Protein	Number of Families and Origin	Allelic Status
  643C>T	6	Missense	R215W	1†             Czech	He*
  657del5     (657_661del5)	6	Frameshift	Truncated     protein (233 aa)	>90%             Slavic             founder mutation	Ho‡             (He)
  681delT	6	Frameshift	Truncated     protein (229 aa)	1             Russian	He
  698del4     (698_701del4)	6	Frameshift	Truncated     protein (236 aa)	2             English	Ho             He
  742insGG     (742_743insGG)	7	Frameshift	Truncated     protein (251 aa)	1             Italian	Ho
  835del4     (835_838del4)	7	Frameshift	Truncated     protein (279 aa)	1     Italian	Ho
  842insT     (842_843insT)	7	Frameshift	Truncated     protein (283 aa)	1             Mexican	Ho
  900del25     (900_924del25)	8	Frameshift	Truncated     protein (305 aa)	1             Moroccan	Ho
  976C>T	8	Nonsense	Q326X	1             Dutch	Ho
  1089C>A	9	Nonsense	Y363X	3       § Pakistani	Ho
  1142delC	10	Frameshift	Truncated     protein (402 aa)	2             Canadian	He

  *He - Heterozygous (compound with 657del5).
  †Monozygotic twin-brothers (compound heterozygotes) with severe disease phenotype³.
  ‡Ho - Homozygous.
  §Three nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA)^{4, 5}.
• Endocrinologic evaluation
   
  
  • Ovarian failure is expected in most female patients with NBS.
  • A study of the pituitary-gonadal axis (ie, plasma concentrations of follicle-stimulating hormone [FSH], luteinizing hormone, and estradiol [E2]) in females reaching pubertal age is recommended. A serum FSH level exceeding 30 IU/L and a low E2 level indicate ovarian failure (hypergonadotropic hypogonadism).
• Systematic screening for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, and hepatitis C virus is recommended (once a year or when infection is suspected).

Imaging Studies

• Because patients with NBS have an inherited hypersensitivity to IR, CT scanning is contraindicated; therefore, MRI and ultrasonography are the methods of choice when imaging studies are necessary.
• • Cranial MRI may reveal CNS developmental abnormalities or solid tumor.
  • MRI of chest or abdomen/pelvis allows demonstration/detection of a tumor mass.
  • Ultrasonography of the abdomen depicts urinary tract abnormalities, multiple or accessory spleens, and enlarged lymph nodes
  • In general, pelvic ultrasonograms in females show small homoechoic ovaries resembling streaks and an infantile uterus.

Histologic Findings

Data yielded from histopathologic analysis of tissue biopsy and autopsy specimens from patients with NBS are limited. Findings suggestive of a lymphoproliferative disorder are the most common indications for lymph node biopsy, but only a few reports on the histologic and immunophenotypic features of lymphomas are available. In 2000, Gladkowska-Dura and Chrzanowska⁶ reported a detailed study of lymphomas in 11 NBS patients.

Although at least 50 patients with NBS are known to have died, extensive autopsy findings are well documented in only 1 patient, and limited information is available in a few others. Markedly reduced brain weight and thymus dysplasia or aplasia were consistent findings in all cases. No cerebellar degeneration was confirmed, which is in contrast to persons with A-T. A detailed neuropathological study of the first-recognized NBS case was reported by Lammens et al⁷ in 2003.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

No specific therapy is available for NBS.

• Substitution with immunoglobulins (ie, intravenous immunoglobulin [IVIG] therapy) is indicated in patients with agammaglobulinemia (serum concentration of IgG <2.5-3 g/L, depending on patient age) and in children with IgG2 deficiency (<0.48 g/L in patients aged 2-5 y and <0.72 g/L in patients >5 y). Before IVIG is started, the presence of anti-IgA antibodies must be determined in patients with IgA deficiency. In such cases, the subcutaneous administration of immunoglobulins is advocated to prevent shock, which can occur in patients with anti-IgA antibodies. A pediatric immunologist must make the decision to start substitution therapy.
• Consider antibiotic prophylaxis in patients with recurrent respiratory tract infections. Urinary tract infections due to congenital malformations of the kidneys occur in some children; antibiotic prophylaxis is indicated in these patients.
• Cancer treatment must be modified in NBS patients with malignancy because conventional doses of radiotherapy and chemotherapy may lead to severe (even lethal/ life-threatening) toxic complications. Curative therapy, however, is possible and should be attempted. The intensity of therapy must be adapted to individual risk factors and tolerance. The use of radiomimetics, alkylating agents, and epipodophyllotoxins should be avoided, and the dose of methotrexate should be limited. Anthracycline-induced cardiomyopathy was reported in one patient, and, therefore, echocardiographic monitoring is strongly recommended.
• Bone marrow transplantation can be considered in some patients. This procedure has been successfully used for a patient with NBS, who was initially diagnosed with atypical FA, in order to correct his severe immunodeficiency.⁵ The child underwent an FA-regimen bone marrow transplantation procedure (with a reduced dose of an alkylating agent and irradiation) by age 3 years. No major complications were observed. The diagnosis was then changed to NBS after a novel homozygous mutation was found in the NBS1 gene. At 3 years posttransplantation, he was stably engrafted with mixed chimerism and had normal humoral and cell-mediated immunity. However, further follow-up is needed to monitor long-term effects, including the development of malignancies.
• Prepubertal female patients with delayed or absent sexual maturation require the systematic care of a (pediatric) endocrinologist, gynecologist, or both. When hypergonadotropic hypogonadism is confirmed (serum FSH level >30 IU/L, low E2 level), substitution hormone therapy to support the development of secondary sex characteristics and to prevent osteoporosis must be considered when the patient reaches the appropriate age.
• Vitamin E supplementation in doses appropriate for age and body weight is recommended, as in individuals with other chromosome instability disorders.

Surgical Care

• Neurosurgical treatment with a ventriculoperitoneal shunt may be necessary for patients with hydrocephaly.
• Surgical repair may also be required in cases of inherited malformations (eg, anal atresia, polydactyly).

Consultations

• Consultations with the following various specialists may be required:
• • Pediatric immunologist
  • Oncologist
  • Pulmonologist
  • Neurologist
  • Endocrinologist
  • Gynecologist
  • Others, as determined by history and physical examination findings
• Offer genetic counseling to provide families with information about the high recurrence risk and the possibility of prenatal diagnosis. NBS is inherited in an autosomal recessive manner. Parents of an affected child are obligate carriers of a single copy of a disease-causing mutation in the NBS1 gene and have a 25% likelihood (1:4) of giving birth to an affected child. Heterozygotes are asymptomatic. However, some reports have suggested an increased risk of malignancy in carriers of the common Slavic mutation, 657del5. Therefore, monitoring parents for malignancy is recommended.
• Delayed speech development is observed in many children, and speech therapy is needed to correct articulation problems.
• Most patients with mental retardation require educational support. They may need to attend special education classes or schools.

Activity

• Infants and young children with NBS demonstrate striking psychomotor hyperactivity and have a short attention span.
• Generally, all children with NBS have a gentle personality and, despite being shy, they are usually capable of good social interactions.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Further inpatient care is needed in some patients with severe recurrent infection.
• Inpatient care is needed in all patients diagnosed with malignancy.

Further Outpatient Care

• Further outpatient care (eg, IVIG therapy, infection treatment) is determined by the degree of immune deficiency and clinical course.
• Periodic follow-up is indicated to monitor immune status, physical growth, and intellectual development.
• Systematic periodic monitoring for malignancy development is mandatory.

Deterrence/Prevention

• Prenatal diagnosis is possible for families with a 25% risk of having an affected child. Molecular genetic analysis is the method of choice. However, the identification of disease-causing mutations in both alleles of the NBS1 gene is necessary before prenatal testing can be performed.
• Fetal DNA is obtained either by chorionic villous sampling at 10-12 weeks' gestation or by early amniocentesis at 13-15 weeks' gestation.

Complications

• Recurrent pneumonia and bronchitis may result in bronchiectasis or respiratory insufficiency.
• Recurrent otitis media may result in draining ear(s) or mastoiditis.
• Malignancies occur frequently in patients with NBS.
• An adverse reaction to radiation therapy, chemotherapy, or both in patients with unrecognized NBS may result in toxic death.
• At least 3 patients who had medulloblastoma and received radiation before being diagnosed with NBS were fatally injured, and they eventually died from complications of the therapy.
• Alopecia was an adverse effect observed in a Polish patient with acute myeloblastic leukemia given an 18-Gy dose of cranial irradiation for CNS prophylaxis. However, another Polish patient manifested no complications after receiving an identical dose by prophylactic cranial irradiation for high-risk group T-cell acute lymphoblastic leukemia. Both patients were treated for the malignancy before the diagnosis of NBS was established.
• Physicians should be aware of the possibility that NBS is underdiagnosed in children with malignant diseases in geographical areas where the disease is less frequent.
• A high index of suspicion is necessary for patients who (1) develop any type of malignancy and have congenital defects (eg, microcephaly) and (2) develop lymphoid malignancy at a very young age (younger than 3 y).

Prognosis

• Currently, the long-term prognosis for patients with NBS appears to be poor.
• Premature death occurs from either aggressive malignancy or complications of infection.
• The patient's life span is reduced significantly; however, survival into the third or fourth decade has been recorded.

Patient Education

• Delayed speech development is observed in many children, and speech therapy is needed to correct articulation problems.
• Most patients with mental retardation require educational support. They may need to attend special education classes or schools.
• To find a genetics or prenatal diagnosis clinic, see GeneTests, Laboratory Directory.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• NBS is a rare autosomal recessive condition of chromosomal instability with immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy. Because NBS is a cutaneous marker for cancer, failure to diagnose NBS can potentially result in legal liability.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
	View Full Size Image
Media type:  Photo

Media file 2:  Lateral facial features with sloping forehead and receding mandible are shown in the same 6-month-old infant as in Media File 1.
	View Full Size Image
Media type:  Photo

Media file 3:  Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
	View Full Size Image
Media type:  Photo

Media file 4:  Lateral profile of the same 9-year-old girl as in Media File 3. This view shows a relatively long nose and receding mandible.
	View Full Size Image
Media type:  Photo

Media file 5:  Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
	View Full Size Image
Media type:  Photo

Media file 6:  Vitiligo spots in a patient with Nijmegen breakage syndrome.
	View Full Size Image
Media type:  Photo

Media file 7:  Progressive vitiligo in a patient with Nijmegen breakage syndrome.
	View Full Size Image
Media type:  Photo

Media file 8:  Café au lait–like spots in a patient with Nijmegen breakage syndrome.
	View Full Size Image
Media type:  Photo

Media file 9:  Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.
	View Full Size Image
Media type:  Photo

Media file 10:  MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Also see Media Files 11-13. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
	View Full Size Image
Media type:  MRI

Media file 11:  MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Also see Media Files 10, 12, and 13. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
	View Full Size Image
Media type:  MRI

Media file 12:  MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Also see Media Files 10, 11, and 13. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
	View Full Size Image
Media type:  MRI

Media file 13:  MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Also see Media Files 10-12. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand. Jul 1981;70(4):557-64. [Medline].
2. Seemanova E, Passarge E, Beneskova D, Houstek J, Kasal P, Sevcikova M. Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet. Apr 1985;20(4):639-48. [Medline].
3. Seemanova E, Sperling K, Neitzel H, Varon R, Hadac J, Butova O, et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. Mar 2006;43(3):218-24. [Medline].
4. Gennery AR, Slatter MA, Bhattacharya A, Barge D, Haigh S, O'Driscoll M, et al. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol. Nov 2004;113(2):214-9. [Medline].
5. New HV, Cale CM, Tischkowitz M, Jones A, Telfer P, Veys P, et al. Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer. May 2005;44(5):494-9. [Medline].
6. Gladkowska-Dura M, Chrzanowska KH, Dura WT. Malignant lymphoma in Nijmegen breakage syndrome. Ann Pediatr Pathol. 2000;4:39-46.
7. Lammens M, Hiel JA, Gabreels FJ, van Engelen BG, van den Heuvel LP, Weemaes CM. Nijmegen breakage syndrome: a neuropathological study. Neuropediatrics. Aug 2003;34(4):189-93. [Medline].
8. Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, et al. Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. J Pediatr Hematol Oncol. Mar 2003;25(3):248-51. [Medline].
9. Barth E, Demori E, Pecile V, Zanazzo GA, Malorgio C, Tamaro P. Anthracyclines in Nijmegen breakage syndrome. Med Pediatr Oncol. Feb 2003;40(2):122-4. [Medline].
10. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, Walecki J, Krajewska-Walasek M, Józwiak S, et al. Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology. Jan 2000;42(1):43-7. [Medline].
11. Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A. Sep 1 2005;137(3):283-7. [Medline].
12. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. May 1 1998;93(3):477-86. [Medline].
13. Cerosaletti KM, Lange E, Stringham HM, Weemaes CM, Smeets D, Sölder B, et al. Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype. Am J Hum Genet. Jul 1998;63(1):125-34. [Medline].
14. Cheung VG, Ewens WJ. Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype. Genome Res. Aug 2006;16(8):973-9. [Medline].
15. Chrzanowska K, Stumm M, Bialecka M, Saar K, Bernatowska-Matuszkiewicz E, Michalkiewicz J, et al. Linkage studies exclude the AT-V gene(s) from the translocation breakpoints in an AT-V patient. Clin Genet. May 1997;51(5):309-13. [Medline].
16. Chrzanowska KH. [Microcephaly with chromosomal instability and immunodeficiency--Nijmegen syndrome]. Pediatr Pol. Mar 1996;71(3):223-34. [Medline].
17. Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M, Bialecka M, Gutkowska A, Goryluk-Kozakiewicz B, et al. Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet. Jul 3 1995;57(3):462-71. [Medline].
18. Chrzanowska KH, Piekutowska-Abramczuk D, Popowska E, Gladkowska-Dura M, Maldyk J, Syczewska M, et al. Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies. Int J Cancer. Mar 1 2006;118(5):1269-74. [Medline].
19. Chrzanowska KH, Romer T, Krajewska-Walasek M. Evidence for a high rate of gonadal failure in female patients with Nijmegen breakage syndrome. Eur J Hum Genet. 2000;8 (Suppl. 1):73.
20. Chrzanowska KH, Stumm M, Bekiesiska-Figatowska M, Varon R, Biaecka M, Gregorek H, et al. Atypical clinical picture of the Nijmegen breakage syndrome associated with developmental abnormalities of the brain. J Med Genet. Jan 2001;38(1):E3. [Medline].
21. Conley ME, Spinner NB, Emanuel BS, Nowell PC, Nichols WW. A chromosomal breakage syndrome with profound immunodeficiency. Blood. May 1986;67(5):1251-6. [Medline].
22. Demuth I, Frappart PO, Hildebrand G, Melchers A, Lobitz S, Stockl L, et al. An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. Hum Mol Genet. Oct 15 2004;13(20):2385-97. [Medline].
23. Di Masi A, Antoccia A, Spadoni E, Varon-Mateeva R, Maraschio P, Tanzarella C. Screening of Nijmegen breakage syndrome 1 mutations in four unrelated families by polymerase chain reaction using sequence-specific primers. Genet Test. 2006;10(1):24-30. [Medline].
24. Digweed M, Sperling K. Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amst). Aug-Sep 2004;3(8-9):1207-17. [Medline].
25. Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol. Jul 2003;41(1):44-8. [Medline].
26. Dumon-Jones V, Frappart PO, Tong WM, Sajithlal G, Hulla W, Schmid G, et al. Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis. Cancer Res. Nov 1 2003;63(21):7263-9. [Medline].
27. Elenitoba-Johnson KS, Jaffe ES. Lymphoproliferative disorders associated with congenital immunodeficiencies. Semin Diagn Pathol. Feb 1997;14(1):35-47. [Medline].
28. Featherstone C, Jackson SP. DNA repair: the Nijmegen breakage syndrome protein. Curr Biol. Aug 27 1998;8(17):R622-5. [Medline].
29. Frappart PO, Tong WM, Demuth I, Radovanovic I, Herceg Z, Aguzzi A, et al. An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med. May 2005;11(5):538-44. [Medline].
30. Gregorek H, Chrzanowska KH, Michalkiewicz J, Syczewska M, Madalinski K. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin Exp Immunol. Nov 2002;130(2):319-24. [Medline].
31. Hibner E, Wendorff J, Ircha G, Piotrowicz M, Zeman K. Cavernous sinus thrombophlebitis in Nijmegen breakage syndrome. Pediatr Neurol. Jul 2002;27(1):62-4. [Medline].
32. Hiel JA, Weemaes CM, van Engelen BG, Smeets D, Ligtenberg M, van Der Burgt I, et al. Nijmegen breakage syndrome in a Dutch patient not resulting from a defect in NBS1. J Med Genet. Jun 2001;38(6):E19. [Medline].
33. Howlett NG, Scuric Z, D'Andrea AD, Schiestl RH. Impaired DNA double strand break repair in cells from Nijmegen breakage syndrome patients. DNA Repair (Amst). Feb 3 2006;5(2):251-7. [Medline].
34. Jaspers NG, Taalman RD, Baan C. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet. Jan 1988;42(1):66-73. [Medline].
35. Kang J, Bronson RT, Xu Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J. Mar 15 2002;21(6):1447-55. [Medline].
36. Kracker S, Bergmann Y, Demuth I, Frappart PO, Hildebrand G, Christine R, et al. Nibrin functions in Ig class-switch recombination. Proc Natl Acad Sci U S A. Feb 1 2005;102(5):1584-9. [Medline].
37. Kruger L, Demuth I, Neitzel H, Varon R, Sperling K, Chrzanowska KH, et al. Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. Carcinogenesis. Jan 2007;28(1):107-11. [Medline].
38. Lahdesmaki A, Taylor AM, Chrzanowska KH, Pan-Hammarström Q. Delineation of the role of the Mre11 complex in class switch recombination. J Biol Chem. Apr 16 2004;279(16):16479-87. [Medline].
39. Maraschio P, Danesino C, Antoccia A, Ricordy R, Tanzarella C, Varon R, et al. A novel mutation and novel features in Nijmegen breakage syndrome. J Med Genet. Feb 2001;38(2):113-7. [Medline].
40. Maraschio P, Spadoni E, Tanzarella C, Antoccia A, Di Masi A, Maghnie M, et al. Genetic heterogeneity for a Nijmegen breakage-like syndrome. Clin Genet. Apr 2003;63(4):283-90. [Medline].
41. Matsuura K, Balmukhanov T, Tauchi H, Weemaes C, Smeets D, Chrzanowska K, et al. Radiation induction of p53 in cells from Nijmegen breakage syndrome is defective but not similar to ataxia-telangiectasia. Biochem Biophys Res Commun. Jan 26 1998;242(3):602-7. [Medline].
42. Matsuura S, Weemaes C, Smeets D, Takami H, Kondo N, Sakamoto S, et al. Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24. Am J Hum Genet. Jun 1997;60(6):1487-94. [Medline].
43. Meyer S, Kingston H, Taylor AM, Byrd PJ, Last JI, Brennan BM, et al. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet. Oct 15 2004;154(2):169-74. [Medline].
44. Michalkiewicz J, Barth C, Chrzanowska K, Gregorek H, Syczewska M, Weemaes CM, et al. Abnormalities in the T and NK lymphocyte phenotype in patients with Nijmegen breakage syndrome. Clin Exp Immunol. Dec 2003;134(3):482-90. [Medline].
45. Michallet AS, Lesca G, Radford-Weiss I, Delarue R, Varet B, Buzyn A. T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome. Ann Hematol. Aug 2003;82(8):515-7. [Medline].
46. Moreno Perez D, Garcia Martin FJ, Vazquez Lopez R, Perez Ruiz E, Gonzalez Valentín ME, Weil Lara B, et al. [Nijmegen breakage syndrome associated with pulmonary lymphoma]. An Esp Pediatr. Dec 2002;57(6):574-7. [Medline].
47. Muschke P, Gola H, Varon R, Ropke A, Zumkeller W, Wieacker P, et al. Retrospective diagnosis and subsequent prenatal diagnosis of Nijmegen breakage syndrome. Prenat Diagn. Feb 2004;24(2):111-3. [Medline].
48. O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. Dec 2001;8(6):1175-85. [Medline].
49. Pasic S. Aplastic anemia in Nijmegen breakage syndrome. J Pediatr. Nov 2002;141(5):742. [Medline].
50. Pasic S, Vujic D, Fiorini M, Notarangelo LD. T-cell lymphoblastic leukemia/lymphoma in Nijmegen breakage syndrome. Haematologica. Aug 2004;89(8):ECR27. [Medline].
51. Petrini JH. The Mre11 complex and ATM: collaborating to navigate S phase. Curr Opin Cell Biol. Jun 2000;12(3):293-6. [Medline].
52. Porcedda P, Turinetto V, Lantelme E, Fontanella E, Chrzanowska K, Ragona R, et al. Impaired elimination of DNA double-strand break-containing lymphocytes in ataxia telangiectasia and Nijmegen breakage syndrome. DNA Repair (Amst). Aug 13 2006;5(8):904-13. [Medline].
53. Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci U S A. Feb 1 2005;102(5):1590-5. [Medline].
54. Resnick IB, Kondratenko I, Togoev O, Vasserman N, Shagina I, Evgrafov O, et al. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr. Mar 2002;140(3):355-61. [Medline].
55. Saar K, Chrzanowska KH, Stumm M, Jung M, Nürnberg G, Wienker TF, et al. The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet. Mar 1997;60(3):605-10. [Medline].
56. Seeman P, Gebertova K, Paderova K, Sperling K, Seemanova E. Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly. Pediatr Neurol. Mar 2004;30(3):195-200. [Medline].
57. Seemanova E, Pohanka V, Seeman P, Misovicova N, Behunova J, Kvasnicova M, et al. [Nijmegen breakage syndrome in Slovakia]. Cas Lek Cesk. 2004;143(8):538-41; discussion 542. [Medline].
58. Seemanova E, Sperling K, Neitzel H, Varon R, Hadac J, Butova O, et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. Mar 2006;43(3):218-24. [Medline].
59. Seidemann K, Henze G, Beck JD, Sauerbrey A, Kühl J, Mann G, et al. Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials. Ann Oncol. 2000;11 Suppl 1:141-5. [Medline].
60. Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet. 1997;31:635-62. [Medline].
61. Shimada H, Shimizu K, Mimaki S, Sakiyama T, Mori T, Shimasaki N, et al. First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability. Hum Genet. Oct 2004;115(5):372-6. [Medline].
62. Stavridi ES, Halazonetis TD. Nbs1 moving up in the world. Nat Cell Biol. Jul 2005;7(7):648-50. [Medline].
63. Stumm M, Gatti RA, Reis A, Udar N, Chrzanowska K, Seemanova E. The ataxia-telangiectasia-variant genes 1 and 2 are distinct from the ataxia-telangiectasia gene on chromosome 11q23.1. Am J Hum Genet. Oct 1995;57(4):960-2. [Medline].
64. Taalman RD, Hustinx TW, Weemaes CM, Seemanova E, Schmidt A, Passarge E, et al. Further delineation of the Nijmegen breakage syndrome. Am J Med Genet. Mar 1989;32(3):425-31. [Medline].
65. Tekin M, Akcayoz D, Ucar C, Gulen H, Akar N. 657del5 mutation of the Nijmegen breakage syndrome gene (NBS1) in the Turkish population. Hum Biol. Jun 2005;77(3):393-7. [Medline].
66. The International Nijmegen Breakage Syndrome Study Group. Nijmegen breakage syndrome. Arch Dis Child. May 2000;82(5):400-6. [Medline].
67. Van de Kaa CA, Weemaes CM, Wesseling P, Schaafsma HE, Haraldsson A, De Weger RA. Postmortem findings in the Nijmegen breakage syndrome. Pediatr Pathol. Sep-Oct 1994;14(5):787-96. [Medline].
68. van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C. Nijmegen breakage syndrome. J Med Genet. Feb 1996;33(2):153-6. [Medline].
69. Varon R, Dutrannoy V, Weikert G, Tanzarella C, Antoccia A, Stockl L, et al. Mild Nijmegen breakage syndrome phenotype due to alternative splicing. Hum Mol Genet. Mar 1 2006;15(5):679-89. [Medline].
70. Varon R, Seemanova E, Chrzanowska K, Hnateyko O, Piekutowska-Abramczuk D, Krajewska-Walasek M, et al. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet. Nov 2000;8(11):900-2. [Medline].
71. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. May 1 1998;93(3):467-76. [Medline].
72. Wang JY. Cancer. New link in a web of human genes. Nature. May 25 2000;405(6785):404-5. [Medline].
73. Weemaes CM, Smeets DF, van der Burgt CJ. Nijmegen Breakage syndrome: a progress report. Int J Radiat Biol. Dec 1994;66(6 Suppl):S185-8. [Medline].
74. Wegner RD, Chrzanowska K, Sperling K, Stumm M. Ataxia-telangiectasia variants (Nijmegen breakage syndrome). In: Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. New York, NY: Oxford University Press; 1999:324-34.
75. Wegner RD, Metzger M, Hanefeld F, Jaspers NG, Baan C, Magdorf K, et al. A new chromosomal instability disorder confirmed by complementation studies. Clin Genet. Jan 1988;33(1):20-32. [Medline].
76. Wilda M, Demuth I, Concannon P, Sperling K, Hameister H. Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. Hum Mol Genet. Jul 22 2000;9(12):1739-44. [Medline].
77. Williams BR, Mirzoeva OK, Morgan WF, Lin J, Dunnick W, Petrini JH. A murine model of Nijmegen breakage syndrome. Curr Biol. Apr 16 2002;12(8):648-53. [Medline].
78. Yang YG, Frappart PO, Frappart L, Wang ZQ, Tong WM. A novel function of DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells and cataractogenesis. DNA Repair (Amst). Aug 13 2006;5(8):885-93. [Medline].
79. Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res. Jan 2006;16(1):45-54. [Medline].

Article Last Updated: Feb 26, 2007